The overall goal of Project 5 is to identify genes and functional polymorphisms that affect quantitative measures of atherosclerosis, NIDDM, and obesity in Mexican American families. The particular focus of Project 3 is on following up significant evidence of linkage and association that has been detected in the current grant period. Two chromosomal regions will be the primary targets of this effort, a region on chromosome 2 that has shown linkage to a quantitative trait locus (QTL) for leptin levels (LOD=7.5) and association between leptin levels and polymorphisms in the pro-opiomelanocortin gene (p<0.005) and a region on chromosome 15 that has shown linkage to a QTL for a variety of HDL size phenotypes (LODs 2.1 to 3.8) and association between these traits and a variant in the promoter region of the hepatic lipase gene (p<0.001). The previously detected associations with strong candidate genes in these two regions will be exploited to focus the initial search on polymorphism in or near these genes. To identify single nucleotide polymorphism (SAPS) in these genes, 20 kb in and around pro-opiomelanocortin and hepatic lipase will be sequenced in 48 individuals from the families that show linkage to these regions and associations with previously typed markers in these genes. All SAPS will be genotyped that have a frequency of at least 5% in the set of 500 individuals in 10 large polymorphism will be initially assessed using combined linkage/disequilibrium and conditional measured genotype methods. When all polymorphism in a given region have been genotype in the 10 large pedigrees, newly developed statistical functional gnomic methods will be applied that are designed to identify functional polymorphism by teasing apart variants which affect the trait from those in linkage disequilibrium with them. SAPS showing evidence of association will be typed in a second set of 500 individuals for replication. Finally, Project 3 will also genotype 50 micro satellite markers in new regions of interest identified by Projects 1 and 2 for purposes of fine-mapping as well as 20 SAPS in positional candidate genes in these new regions.